SummaryThe precisionFDA Truth Challenge V2 aimed to assess the state-of-the-art of variant calling in difficult-to-map regions and the Major Histocompatibility Complex (MHC). Starting with FASTQ files, 20 challenge participants applied their variant calling pipelines and submitted 64 variant callsets for one or more sequencing technologies (~35X Illumina, ~35X PacBio HiFi, and ~50X Oxford Nanopore Technologies). Submissions were evaluated following best practices for benchmarking small variants with the new GIAB benchmark sets and genome stratifications. Challenge submissions included a number of innovative methods for all three technologies, with graph-based and machine-learning methods scoring best for short-read and long-read datasets, respectively. New methods out-performed the 2016 Truth Challenge winners, and new machine-learning approaches combining multiple sequencing technologies performed particularly well. Recent developments in sequencing and variant calling have enabled benchmarking variants in challenging genomic regions, paving the way for the identification of previously unknown clinically relevant variants.
SUMMARYDuring the last decade, the identification of a number of novel drug targets led to the development of promising new compounds which are currently under evaluation for their therapeutic prospective in CNS related disorders. Besides the established pleiotropic regulatory functions in the periphery, the interest in the potential homeostatic role of histamine in the brain was revived following the identification of H 3 and H 4 receptors some years ago. Complementing classical CNS pharmacology, the development of selective histamine receptor agonists, antagonists, and inverse agonists provides the lead for the potential exploitation of the histaminergic system in the treatment of brain pathologies. Although no CNS disease entity has been associated directly to brain histamine dysfunction until now, the H 3 receptor is recognized as a drug target for neuropathic pain, sleep-wake disorders, including narcolepsy, and cognitive impairment associated with attention deficit hyperactivity disorder, schizophrenia, Alzheimer's, or Parkinson's disease, while the first H 3 receptor ligands have already entered phase I-III clinical trials. Interestingly, the localization of the immunomodulatory H 4 receptor in the nervous system exposes attractive perspectives for the therapeutic exploitation of this new drug target in neuroimmunopharmacology. This review focuses on a concise presentation of the current "translational research" approach that exploits the latest advances in histamine pharmacology for the development of beneficial drug targets for the treatment of neuronal disorders, such as neuropathic pain, cognitive, and sleep-wake pathologies. Furthermore, the role of the brain histaminergic system(s) in neuroprotection and neuroimmunology/inflammation remains a challenging research area that is currently under consideration.
AtoS-AtoC two-component system acts directly on the atoDAEB operon transcription to regulate the biosynthesis of short-chain poly-(R)-3-hydroxybutyrate. This study sought to investigate the effect of histamine and compound 48/80 on the regulation of AtoS-AtoC two-component system in Escherichia coli K-12 MA255 (speC(-), speB(-)) and the isogenic E. coli strains BW25113 (atoSC(+)) and BW28878 (DeltaatoSC) transformed with plasmids carrying related genes. Histamine or compound 48/80 induced or tended to reduce atoC transcription, respectively, while neither compound showed any effect on atoDAEB operon transcription. Moreover, histamine down-regulated poly-(R)-3-hydroxybutyrate biosynthesis, whereas compound 48/80 up-regulated its biosynthesis, maximal induction being obtained in the presence of multiple copies of AtoS-AtoC. Interestingly, co-administration of histamine counteracted this inductive effect of compound 48/80. The reported data provide the first evidence for a differential modulator role of histamine and compound 48/80 on the AtoS-AtoC two-component system signaling in potentially pathogenic bacteria, leading to a new perspective on their symbiotic behavior.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.